Ras oncogene undergoes point mutation in many tumor tissues in humans and is detected as an activated form capable of transforming normal cells. It is essential for the expression of transforming activity of the ras oncogene product that the 12th, 13th or 61st amino acid should undergo point mutation and, additionally, the cysteine residue at the C terminal region should be farnesylated for the membrane association of the ras oncogene product. The reaction is catalyzed by farnesyltransferase (hereinafter referred to as "FTase"). Accordingly, an FTase inhibitor is expected to inhibit the function of the ras oncogene product and thereby to have antitumor activity.
Compounds represented by the following formulae are known as expoxycyclohexene derivatives having FTase inhibitory activity. ##STR3##
Manumycin [Proc. Natl. Acad. Sci. USA, 90, 2281 (1993)]. It is reported that IC50 against FTase of yeast origin is 5 .mu.mol when ras protein of yeast origin is used as a substrate. ##STR4##
Manumycin derivatives (compounds IVa, IVb, and IVc) [Proc. Natl. Acad. Sci. USA, 90, 2281 ( 1993 ); Tetrahedron Letters, (1973); J. Antibiotics, 40, 1530 and 1549 (1987); Japanese Patent Application No. 2-120640, published as unexamined Laid-Open application No. 221377/1992 (U.S. Pat. No. 5,106,868). It is reported that the activity of these compounds can be detected, and that the activity is not numerically described.
An epoxycyclohexenedione derivative represented by the following formula is known, but FTase inhibitory activity of the compound is not reported: ##STR5## Askamycin derivative [J.Am. Chem. Soc., 101, 3402 (1979)]. ##STR6##
LL-C10037 a derivative [J. Am. Chem. Soc., 111., 7932 (1989), J. Org. Chem., 59, 3518 (1994)].